WO2023088436A1 - 抗pd-1抗体和抗vegf-a抗体的药物组合及其使用方法 - Google Patents

抗pd-1抗体和抗vegf-a抗体的药物组合及其使用方法 Download PDF

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WO2023088436A1
WO2023088436A1 PCT/CN2022/132913 CN2022132913W WO2023088436A1 WO 2023088436 A1 WO2023088436 A1 WO 2023088436A1 CN 2022132913 W CN2022132913 W CN 2022132913W WO 2023088436 A1 WO2023088436 A1 WO 2023088436A1
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antibody
vegf
seq
pemetrexed
administered
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PCT/CN2022/132913
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English (en)
French (fr)
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王树彦
张文
张成丽
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信达生物制药(苏州)有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the invention discloses a drug combination comprising an anti-PD-1 antibody and one or more chemotherapeutic agents, the drug combination may further comprise an anti-VEGF-A antibody, and the drug combination is used to prevent or treat cancer.
  • the invention also discloses the use and method of using the composition product to prevent or treat cancer.
  • Non-small cell lung cancer accounts for about 80% to 85% of all lung cancer cases, and about 70% of NSCLC patients are locally advanced or metastatic diseases that are not suitable for surgical resection at the time of diagnosis.
  • NSCLC patients with advanced driver gene positive can use corresponding targeted therapy.
  • the positive rate of EGFR gene mutation in Asian population and Chinese patients with lung adenocarcinoma is 48.5% (Gou LY, Wu YL. Prevalence of driver mutations in non-small-cell lung cancers in the People'S Republic of China. Lung Cancer Target Therapy, 2014 ).
  • Tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, or icotinib) are recommended as first-line treatment for advanced NSCLC patients with EGFR mutations. Progression after first- and second-generation TKI treatment, if there is a T790M mutation, third-generation TKI (osimertinib, etc.) can be used for treatment. If the T790M mutation is negative or progresses after osimertinib treatment, platinum-based double-drug chemotherapy is recommended for systemic treatment (Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Primary Lung Cancer 2018 Edition).
  • CSCO Clinical Oncology
  • the present invention discloses a pharmaceutical combination comprising an anti-PD-1 antibody and one or more chemotherapeutic agents.
  • the present invention also discloses a pharmaceutical combination comprising an anti-PD-1 antibody, an anti-VEGF-A antibody and one or more chemotherapeutic agents.
  • the drug combination of therapeutic agents in addition, the present invention also discloses the use of the drug combination, and the method of using the drug combination to treat lung cancer, such as the treatment of non-small cell lung cancer, especially the treatment of local EGFR mutations that fail EGFR-TKI treatment. Advanced or metastatic nonsquamous non-small cell lung cancer.
  • the present invention also provides a method of administration, which includes a combined treatment period and a maintenance treatment period, and the method of administration can be used for the treatment of lung cancer, such as the treatment of non-small cell lung cancer, especially for EGFR mutations that fail EGFR-TKI treatment. Locally advanced or metastatic nonsquamous non-small cell lung cancer.
  • the term “comprising” or “comprising” means including stated elements, integers or steps, but not excluding any other elements, integers or steps.
  • the term “comprising” or “comprising” is used, unless otherwise specified, it also covers the situation of combining the mentioned elements, integers or steps.
  • an antibody variable region that "comprises” a particular sequence it is also intended to encompass an antibody variable region that consists of that particular sequence.
  • “Individual” includes mammals. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., , mice and rats). In some embodiments, the individual is a human, including a child, adolescent, or adult.
  • domesticated animals e.g., cattle, sheep, cats, dogs, and horses
  • primates e.g., humans and non-human primates such as monkeys
  • rabbits e.g., mice and rats
  • rodents e.g., mice and rats.
  • the individual is a human, including a child, adolescent, or adult.
  • administered in combination refers to the administration of two or more therapeutic agents to treat a disease as described herein.
  • Such administration includes co-administration of the therapeutic agents in a substantially simultaneous manner, eg, in a single composition with fixed ratios of the active ingredients.
  • such administration includes co-administration for each active ingredient in multiple or in separate containers (eg tablets, capsules, powders and liquids). Powders and/or liquids can be reconstituted or diluted to the desired dosage before administration.
  • such administration also includes using each type of therapeutic agent in a sequential manner at about the same time or at different times. In either case, the treatment regimen will provide for the beneficial effect of the drug combination in treating the disorders or conditions described herein.
  • treating means slowing, interrupting, arresting, alleviating, stopping, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.
  • prevention includes the inhibition of the occurrence or development of a disease or disorder or a symptom of a particular disease or disorder.
  • individuals with a family history of the disease are candidates for prophylactic regimens.
  • prophylactic regimens refers to the administration of a drug prior to the onset of signs or symptoms, especially in at-risk individuals.
  • an effective amount refers to the amount or dose of a formulation or composition of the invention which, when administered to a patient in single or multiple doses, produces the desired effect in the treated patient.
  • An effective amount can be readily determined by the attending physician, who is skilled in the art, by considering various factors such as the species of the mammal; its size, age and general health; the particular disease involved; the extent or severity of the disease; the individual patient's response; the particular antibody administered; the mode of administration; the bioavailability characteristics of the formulation administered; the chosen dosing regimen; and the use of any concomitant therapy.
  • composition refers to a composition comprising at least one active ingredient or active ingredients suitable for administration to an animal, preferably a mammal, including a human.
  • the term "margin of superiority” The purpose of the superiority test is to show that the drug under study is more effective than the control drug (active drug or placebo control), inferring clinically meaningful superiority, it is necessary to determine the clinically acceptable This cutoff is called the superiority cutoff.
  • the present invention provides a pharmaceutical combination comprising an anti-PD-1 antibody and one or more chemotherapeutic agents.
  • the present invention provides a pharmaceutical combination comprising anti-PD-1 antibody, anti-VEGF-A antibody and one or more chemotherapeutic agents.
  • the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises HCDR1, HCDR2, HCDR3, and the light chain comprises LCDR1, LCDR2, LCDR3, wherein:
  • HCDR1 comprises or consists of amino acids shown in SEQ ID NO: 1 (KASGGTFSSYAIS);
  • HCDR2 comprises or consists of amino acids shown in SEQ ID NO: 2 (LIIPMFDTAGYAQKFQG);
  • HCDR3 comprises or consists of amino acids shown in SEQ ID NO: 3 (ARAEHSSTGTFDY);
  • LCDR1 comprises or consists of amino acids shown in SEQ ID NO: 4 (RASQGISSWLA);
  • LCDR2 comprises or consists of amino acids shown in SEQ ID NO:5 (SAASSLQS);
  • LCDR3 comprises or consists of the amino acid shown in SEQ ID NO: 6 (QQANHLPFT).
  • the anti-PD-1 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence shown in SEQ ID NO: 7, or comprises An amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:7, or derived from SEQ ID NO:7 Composition;
  • the VL comprises the amino acid sequence shown in SEQ ID NO:8, or comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% of SEQ ID NO:8 , an amino acid sequence with 98% or 99% identity, or consisting of SEQ ID NO:8.
  • the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence shown in SEQ ID NO: 9, or comprises at least 90% of SEQ ID NO: 9, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical amino acid sequence, or consists of SEQ ID NO: 9; said light chain comprises SEQ ID NO: The amino acid sequence shown in 10, or comprising amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 10 The sequence may consist of SEQ ID NO:10.
  • the anti-VEGF-A antibody is bevacizumab.
  • the one or more chemotherapeutic agents are pemetrexed, platinum-based drugs.
  • the platinum is cisplatin.
  • the dose of anti-PD-1 antibody in the pharmaceutical combination is 50-500 mg, preferably 50 mg, 60 mg, 70 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, more preferably 200mg.
  • the dose of anti-VEGF-A antibody in the pharmaceutical combination is 1-20 mg/kg, preferably 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, 12mg/kg, 14mg/kg, 15mg/kg, 16mg/kg, 18mg/kg, 20mg/kg, more preferably 15mg/kg; or anti-VEGF-
  • the dose of antibody A is 60-1200 mg, preferably 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, 600 mg, 720 mg, 840 mg, 900 mg, 960 mg, 1080 mg, 1200 mg, more preferably 900 mg.
  • the dose of pemetrexed in the medicament is 200-600 mg/m 2 , such as 200 mg/m 2 , 300 mg/m 2 , 400 mg/m 2 , 450 mg/m 2 , 500 mg/m 2 , or any conventional dosage in the prior art.
  • the dose of cisplatin in the drug is 50-100, such as 50 mg/m 2 , 60 mg/m 2 , 70 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , or any existing Usual dosage in technology.
  • the frequency of administration of the pharmaceutical combination is once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks or once every six weeks, preferably once every three weeks.
  • intravenous administration of said pharmaceutical combination is provided.
  • the anti-PD-1 antibody, anti-VEGF-A antibody and chemotherapeutic agent contained in the pharmaceutical combination can be administered simultaneously, separately or sequentially.
  • the anti-PD-1 antibody, anti-VEGF-A antibody, and chemotherapeutic agent are administered sequentially.
  • the anti-PD-1 antibody is administered first, followed by the anti-VEGF-A antibody, followed by the chemotherapeutic agent.
  • anti-PD-1 antibody is administered first, anti-VEGF-A antibody is administered 0.5-24 hours later (preferably anti-VEGF-A antibody is administered for 30-60 minutes), and chemotherapeutic agent is administered 0.5-24 hours later.
  • the present invention provides a kit comprising an effective amount of an anti-PD-1 antibody and an effective amount of a chemotherapeutic agent.
  • the kit provided by the present invention further comprises an effective amount of anti-VEGF-A antibody.
  • each active ingredient of the kit is stored in a separate container.
  • the anti-PD-1 antibody in the complete kit comprises HCDR1, HCDR2, HCDR3 shown in SEQ ID NO:1, 2, 3 and LCDR1, LCDR2 shown in SEQ ID NO: 4, 5, 6 , LCDR3.
  • the anti-PD-1 antibody in the kit comprises the VH shown in SEQ ID NO:7 and the VL shown in SEQ ID NO:8.
  • the anti-PD-1 antibody in the kit of parts comprises the heavy chain shown in SEQ ID NO:9 and the light chain shown in SEQ ID NO:10.
  • the kit of parts comprises 50 mg, 60 mg, 70 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg or 500 mg of an anti-PD-1 antibody.
  • the anti-VEGF-A antibody in the kit of parts is bevacizumab.
  • the kit of parts comprises 60 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, 600 mg, 720 mg, 840 mg, 900 mg, 960 mg, 1080 mg or 1200 mg of an anti-VEGF-A antibody.
  • the chemotherapeutic agents in the kit are preferably pemetrexed, cisplatin.
  • the dose of pemetrexed in the kit is 200-600 mg/m 2 , such as 200 mg/m 2 , 300 mg/m 2 , 400 mg/m 2 , 450 mg/m 2 , 500 mg/m 2 m 2 , or any conventional dosage in the prior art.
  • the dose of cisplatin in the kit is 50-100, such as 50 mg/m 2 , 60 mg/m 2 , 70 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , or any Conventional dosage in the prior art.
  • the kit of parts further comprises a package insert with printed instructions for using the combination of an anti-PD-1 antibody and an anti-VEGF-A antibody to prevent or treat cancer in an individual.
  • the present invention provides a method for preventing or treating tumors in a subject, comprising administering the pharmaceutical combination or kit of the present invention to the subject.
  • the method of treatment comprises 2 administration phases:
  • anti-PD-1 antibody, anti-VEGF-A antibody and chemotherapeutic agent are sequentially administered to the subject; or anti-PD-1 antibody and chemotherapeutic agent are sequentially administered to the subject.
  • the method of treatment comprises 2 administration phases:
  • anti-PD-1 antibody, anti-VEGF-A antibody, pemetrexed and platinum drugs are sequentially administered to the subject; or anti-PD-1 antibody, pemetrexed are sequentially administered to the subject plugged and platinum-based drugs, and
  • anti-PD-1 antibody, anti-VEGF-A antibody and pemetrexed are sequentially administered to the subject; or anti-PD-1 antibody and pemetrexed are sequentially administered to the subject.
  • the platinum drug is cisplatin.
  • the first phase is a combination treatment phase and the second phase is a maintenance treatment phase.
  • the method of treatment includes:
  • Phase 1 combined treatment period in which subjects are sequentially administered anti-PD-1 antibody, anti-VEGF-A antibody, pemetrexed and platinum drugs, and
  • anti-PD-1 antibody, anti-VEGF-A antibody and pemetrexed are sequentially administered to the subject.
  • the platinum drug is cisplatin.
  • the single administration dose of the anti-VEGF-A antibody is 15 mg/kg
  • the single administration dose of the anti-PD-1 antibody is 200 mg
  • the single administration dose of pemetrexed is 500mg/m 2
  • the single dose of cisplatin is 75mg/m 2 .
  • the combined treatment period includes 4 cycles, wherein every three weeks is a treatment cycle, and the drugs are administered sequentially on the first day of each cycle.
  • the subject receives up to 4 cycles of cisplatin
  • the other pharmaceutical ingredients such as anti-PD-1 antibody, anti-VEGF-A antibody and pemetrexed, are administered continuously.
  • all subjects are treated for up to 24 months.
  • the tumor is lung cancer, preferably, the lung cancer is non-small cell lung cancer, more preferably, the non-small cell lung cancer is epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI ) locally advanced or metastatic nonsquamous non-small cell lung cancer with EGFR mutation that failed treatment.
  • EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor
  • the method of treatment provided by the invention obtains the following benefits:
  • the progression-free survival (PFS) of the subject has improved, for example, there is a significantly improved progression-free survival compared with the chemotherapy treatment group using pemetrexed and cisplatin;
  • ORR objective response rate
  • the subject has an improved duration of response (DOR), eg, significantly improved progression-free survival relative to the chemotherapy treatment group with pemetrexed and cisplatin.
  • DOR duration of response
  • the present invention provides the use of the above-mentioned drug combination or kit for treating tumors.
  • the present invention provides the use of the above drug combination or kit in the preparation of drugs for preventing or treating tumors.
  • the tumor is lung cancer, preferably, the lung cancer is non-small cell lung cancer, more preferably, the non-small cell lung cancer is epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI ) locally advanced or metastatic nonsquamous non-small cell lung cancer with EGFR mutation that failed treatment.
  • EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor
  • the pharmaceutical combination or kit of the present invention can obtain the following benefits:
  • the progression-free survival (PFS) of the subject has improved, for example, there is a significantly improved progression-free survival compared with the chemotherapy treatment group using pemetrexed and cisplatin;
  • ORR objective response rate
  • the subject has an improved duration of response (DOR), eg, significantly improved progression-free survival relative to the chemotherapy treatment group with pemetrexed and cisplatin.
  • DOR duration of response
  • Anti-PD-1 antibody sintilimab injection, Innovent Biopharmaceutical (Suzhou) Co., Ltd., specification: 10ml: 100mg.
  • Anti-VEGF-A antibody bevacizumab injection, manufacturer: Innovent Biopharmaceutical (Suzhou) Co., Ltd. Specifications: 4ml: 100mg.
  • Cisplatin 10 mg or 20 mg in multi-dose vials
  • Placebo 1 Sodium citrate (dihydrate): 5.88mg/ml
  • Polysorbate 80 0.2mg/ml
  • Citric acid (monohydrate): appropriate amount, adjust the pH to 6.0
  • Placebo 2 Sodium acetate: 1.64mg/ml
  • Polysorbate 80 Polysorbate 80: 2mg/ml
  • Glacial acetic acid adjust pH to 5.2
  • EGFR mutations were confirmed by tumor histology, cytology or hematology before EGFR-TKI treatment;
  • EGFR-TKI 1st or 2nd generation EGFR-TKI (such as: icotinib, gefitinib, erlotinib, afatinib or other 1st or 2nd generation drugs that have been marketed in China EGFR-TKI) treatment and failure, it needs to be confirmed by histology that the EGFR20 exon T790M mutation is negative;
  • EGFR-TKI 1st or 2nd generation EGFR-TKI (such as: icotinib, gefitinib, erlotinib, afatinib) therapy, histological or Hematology confirmed the presence of EGFR exon 20 T790M mutation positive, followed by treatment with the third generation EGFR-TKI (such as: osimertinib or other third generation EGFR-TKIs that have been marketed in China) and failed; (if the first If there is no T790M test result after the failure of the first-generation or second-generation EGFR-TKI treatment, the disease progression must be met after taking the third-generation EGFR-TKI that has been marketed for more than 6 months; if the first-generation or second-generation EGFR-TKI treatment fails and no As a result of T790M test, it is still effective to switch to the marketed third-generation EGFR-TKI after taking the third-generation EGFR-TKI in the clinical research and
  • EGFR-TKI (such as: osimertinib or other third-generation EGFR-TKIs that have been marketed in China) treatment and failed when EGFR-mutant NSCLC was first diagnosed;
  • the target lesion There must be at least one measurable lesion as the target lesion (according to RECIST V1.1), and the measurable lesion located in the radiation field of previous radiotherapy or after local treatment can also be selected as the target lesion if it is confirmed to progress;
  • ANC absolute neutrophil count
  • PHT platelet count
  • HGB hemoglobin
  • Liver function total bilirubin (TBIL) ⁇ 1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in subjects without liver metastases ⁇ 2.5 times ULN, ALT and AST of subjects with liver metastases ⁇ 5 times ULN;
  • TBIL total bilirubin
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • Renal function serum creatinine (Cr) ⁇ 1.5 times ULN or Cr clearance rate ⁇ 60mL/min (Cockcroft-Gault formula), and urine routine test results show urinary protein (UPRO) ⁇ 2+ or 24-hour urine protein quantitative ⁇ 1g;
  • the urine or serum pregnancy test should be negative within 3 days before receiving the first study drug administration (cycle 1, day 1). If the urine pregnancy test result cannot be confirmed as negative, a blood pregnancy test is requested;
  • This study is a clinical trial evaluating sintilimab ⁇ bevacizumab combined with pemetrexed and cisplatin in patients with EGFR mutations who have failed epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy.
  • EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor
  • the first stage is a first stage
  • Anti-injection has clinically significant PFS benefit, which is better than pemetrexed and cisplatin chemotherapy combination, and also shows a better benefit trend than sintilimab combined with chemotherapy three-drug combination.

Abstract

提供抗PD-1抗体和一种或多种化学治疗剂的药物组合，该药物组合还可进一步包含抗VEGF-A抗体；还提供使用所述药物组合来预防或治疗癌症的用途和方法。

Description

抗PD-1抗体和抗VEGF-A抗体的药物组合及其使用方法 技术领域
本发明公开了包括抗PD-1抗体和一种或多种化学治疗剂的药物组合，该药物组合还可进一步包含抗VEGF-A抗体，以及利用药物组合预防或治疗癌症。本发明还公开了使用所述组合物产品来预防或治疗癌症的用途和方法。
发明背景
随着人类平均寿命的延长和生活行为方式的改变，恶性肿瘤已成为严重威胁人类健康的重要疾病，也是对人类生命威胁最大的疾病。依据2017年2月国家癌症中心发布的数据，中国每年有429万新发癌症病例和281万癌症死亡病例，相当于每天有12000人罹患癌症，有7500人因癌去世。而随着我国人口老龄化的进一步发展，癌症发病率与死亡率仍将继续攀升。在所有癌症死因中，肺癌(25.2％)占第一位，然后依次为肝癌(14.4％)、胃癌(14.3％)和食管癌(9.3％)，这4类癌症的预后差，占所有癌症死亡的63.2％(2017年中国肿瘤登记年报.卫生部疾病预防控制局国家癌症中心,2017)。
在所有肺癌病例中非小细胞肺癌(NSCLC)大约占80％至85％，约70％的NSCLC患者在诊断时已是不适于手术切除的局部晚期或转移性疾病。晚期驱动基因阳性的NSCLC患者可使用对应的靶向治疗。亚裔人群和我国的肺腺癌患者EGFR基因突变阳性率为48.5％(Gou LY,Wu YL.Prevalence of driver mutations in non-small-cell lung cancers in the People’S Republic of China.Lung Cancer Target Therapy,2014)。EGFR突变的晚期NSCLC患者一线推荐使用酪氨酸激酶抑制剂(TKI)(吉非替尼、厄洛替尼或埃克替尼)。一、二代TKI治疗后进展，如果存在T790M突变，可以使用三代TKI(奥希替尼等)治疗。如果T790M突变阴性或者奥希替尼治疗后进展，系统治疗的选择推荐含铂双药化疗(中国临床肿瘤学会(CSCO)原发性肺癌诊疗指南2018版)。对于此类患者，疗效仍需进一步提高(Mok TSK1,Kim SW1,Wu YL et al,Gefitinib Plus Chemotherapy Versus Chemotherapy in Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer Resistant to First-Line Gefitinib(IMPRESS):Overall Survival and Biomarker Analyses.J Clin Oncol.2017Dec 20；35(36):4027-4034)，临床上迫切需要新的治疗选择。欧洲肿瘤内科学会(ESMO)第三十五届年会发布了贝伐珠单抗联合铂化疗一线治疗晚期非鳞状NSCLC的Meta分析结果。证实以贝伐珠单抗为基础的化疗治疗晚期非鳞状NSCLC患者可以获得显著的生存获益、延长缓解时间和预期的安全性，中山大学对贝伐珠单抗联合化疗治疗EGFR-TKI耐药的非鳞状非小细胞肺癌的疗效和安全性进行研究(Sun Yat-sen University,Efficacy and Safety Study of Bevacizumab Plus Chemotherapy in  EGFR-TKI Resistant Non-Squamous Non-Small Cell Lung Cancer.ClinicalTrials.gov,NCT02139579,2014)，结果暂未可知，针对此类患者在免疫治疗方面需进一步研究，免疫联合组治疗，提供了一种有可能改善此类患者的替代治疗方法。
发明内容
本发明公开了包含抗PD-1抗体和一种或多种化学治疗剂的药物组合，优选地，本发明还公开了包含抗PD-1抗体、抗VEGF-A抗体和一种或多种化学治疗剂的药物组合，此外，本发明还公开了所述药物组合的用途，以及利用该药物组合治疗肺癌的方法，例如治疗非小细胞肺癌，尤其是治疗EGFR-TKI治疗失败的EGFR突变的局部晚期或转移性非鳞非小细胞肺癌。
本发明还提供了一种给药方法，该方法包括联合治疗期和维持治疗期，该给药方法可以用于治疗肺癌，例如治疗非小细胞肺癌，尤其是EGFR-TKI治疗失败的EGFR突变的局部晚期或转移性非鳞非小细胞肺癌。
发明详述
1)术语定义
除非另有定义，否则本文中使用的所有技术和科学术语均具有与本领域一般技术人员通常所理解的含义相同的含义。为了本发明的目的，下文定义了以下术语。
如本文所用，术语“和/或”是指可选项中的任一项或可选项的两项或更多项
如本文所用，术语“包含”或“包括”是指包括所述的要素、整数或步骤，但是不排除任意其他要素、整数或步骤。在本文中，当使用术语“包含”或“包括”时，除非另有指明，否则也涵盖由所述及的要素、整数或步骤组合的情形。例如，当提及“包含”某个具体序列的抗体可变区时，也旨在涵盖由该具体序列组成的抗体可变区。
“个体”包括哺乳动物。哺乳动物包括但不限于，家养动物(例如，牛，羊，猫，狗和马)，灵长类动物(例如，人和非人灵长类动物如猴)，兔，以及啮齿类动物(例如，小鼠和大鼠)。在一些实施方案中，个体是人，包括儿童、青少年或成人。
术语“组合施用”是指施用两种或更多种治疗剂以治疗如本发明所述的疾病。这种施用包括以基本上同时的方式共同施用这些治疗剂，例如以具有固定比例的活性成分的单一组合物。或者，这种施用包括对于各个活性成分在多种或在分开的容器(例如片剂、胶囊、粉末和液体)中的共同施用。粉末和/或液体可以在施用前重构或稀释至所需剂量。此外，这种施用还包括以大致相同的时间或在不同的时间以顺序的方式使用每种类型的治疗剂。在任一情况下，治疗方 案将提供药物组合在治疗本文所述的病症或病状中的有益作用。
用于本文时，“治疗”指减缓、中断、阻滞、缓解、停止、降低、或逆转已存在的症状、病症、病况或疾病的进展或严重性。
用于本文时，“预防”包括对疾病或病症或特定疾病或病症的症状的发生或发展的抑制。在一些实施方式中，具有家族病史的个体是预防性方案的候选。通常，术语“预防”是指在病征或症状发生前，特别是在具有风险的个体中发生前的药物施用。
术语“有效量”指本发明的制剂或组合物的量或剂量，其以单一或多次剂量施用患者后，在治疗的患者中产生预期效果。有效量可以由作为本领域技术人员的主治医师通过考虑以下多种因素来容易地确定：诸如哺乳动物的物种；它的大小、年龄和一般健康；涉及的具体疾病；疾病的程度或严重性；个体患者的应答；施用的具体抗体；施用模式；施用制剂的生物利用率特征；选择的给药方案；和任何伴随疗法的使用。
如文中所用，术语“药物组合物”指适合于向动物优选哺乳动物(包括人)施用的包含至少一种活性成分或多种活性成分的组合物。
术语“约”在与数字数值联合使用时意为涵盖具有比指定数字数值小10％的下限和比指定数字数值大10％的上限的范围内的数字数值。
术语“优效性界值”优效性检验的目的是显示所研究的药物效果优于对照药物(阳性药或安慰剂对照)，推断具有临床意义的优效性，需要确定临床上可以接受的界值，这个界值称为优效界值。
缩略语
Figure PCTCN2022132913-appb-000001
Figure PCTCN2022132913-appb-000002
2)药物组合
本发明提供了一种药物组合，其包括抗PD-1抗体和一种或多种化学治疗剂。
在一个优选的实施方案中，本发明提供了一种药物组合，其包括抗PD-1抗体、抗VEGF-A抗体和一种或多种化学治疗剂。
在一个实施方案中，所述抗PD-1抗体包含重链和轻链，其中所述重链包含HCDR1、HCDR2、 HCDR3，所述轻链包含LCDR1、LCDR2、LCDR3，其中：
HCDR1包含SEQ ID NO:1(KASGGTFSSYAIS)所示的氨基酸或由其组成；
HCDR2包含SEQ ID NO:2(LIIPMFDTAGYAQKFQG)所示的氨基酸或由其组成；
HCDR3包含SEQ ID NO:3(ARAEHSSTGTFDY)所示的氨基酸或由其组成；
LCDR1包含SEQ ID NO:4(RASQGISSWLA)所示的氨基酸或由其组成；
LCDR2包含SEQ ID NO:5(SAASSLQS)所示的氨基酸或由其组成；
LCDR3包含SEQ ID NO:6(QQANHLPFT)所示的氨基酸或由其组成。
在一个实施方式中，所述抗PD-1抗体包含重链可变区(VH)和轻链可变区(VL)，其中所述VH包含SEQ ID NO:7所示的氨基酸序列，或包含与SEQ ID NO:7具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一性的氨基酸序列，或由SEQ ID NO:7组成；所述VL包含SEQ ID NO:8所示的氨基酸序列，或包含与SEQ ID NO:8具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一性的氨基酸序列，或由SEQ ID NO:8组成。
Figure PCTCN2022132913-appb-000003
在一个实施方式中，所述抗PD-1抗体包含重链和轻链，其中所述重链包含SEQ ID NO:9所示的氨基酸序列，或包含与SEQ ID NO:9具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一性的氨基酸序列，或由SEQ ID NO:9组成；所述轻链包含SEQ ID NO:10所示的氨基酸序列，或包含与SEQ ID NO:10具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一性的氨基酸序列或由SEQ ID NO:10组成。
Figure PCTCN2022132913-appb-000004
Figure PCTCN2022132913-appb-000005
在一个实施方案中，所述抗VEGF-A抗体为贝伐珠单抗。
在一个实施方式中，所述一种或多种化学治疗剂为培美曲塞、铂类药物。在一个优选实施方案中，所述铂类为顺铂。
在一个实施方式中，所述药物组合中抗PD-1抗体的剂量为50-500mg，优选50mg、60mg、70mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg，更优选200mg。
在一个实施方式中，所述药物组合中抗VEGF-A抗体的剂量为1-20mg/kg，优选1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg、12mg/kg、14mg/kg、15mg/kg、16mg/kg、18mg/kg、20mg/kg，更优选15mg/kg；或抗VEGF-A抗体剂量为60-1200mg，优选60mg、120mg、180mg、240mg、300mg、360mg、420mg、480mg、540mg、600mg、720mg、840mg、900mg、960mg、1080mg、1200mg，更优选900mg。
在一个实施方案中，所述药物中的培美曲塞的剂量为200-600mg/m 2，例如200mg/m 2、300mg/m 2、400mg/m 2、450mg/m 2、500mg/m 2，或任何现有技术中的常规剂量。
在一个实施方案中，所述药物中的顺铂的剂量为50-100，例如50mg/m 2、60mg/m 2、70mg/m 2、75mg/m 2、80mg/m 2，或任何现有技术中的常规剂量。
在一个实施方案中，所述药物组合的施用频率是每周一次、每两周一次、每三周一次、每四周一次、每五周一次或每六周一次，优选为每三周一次。
在一个实施方案中，提供静脉注射施用所述药物组合。
在一个实施方案中，所述药物组合所包含的抗PD-1抗体，抗VEGF-A抗体，化学治疗剂可以同时给药、分开给药或依次给药。
在一个实施方案中，依次给药抗PD-1抗体，抗VEGF-A抗体，化学治疗剂。优选地，先施用抗PD-1抗体后再施用抗VEGF-A抗体，随后再施用化学治疗剂。更优选地先施用抗PD-1抗体，0.5-24小时后再施用抗VEGF-A抗体(优选施用抗VEGF-A抗体30～60分钟)，0.5-24小时后再施用化学治疗剂。
3)成套药盒
在一个实施方式中，本发明提供了一种成套药盒，其中包含有效量的抗PD-1抗体和有效量的化学治疗剂。在一个优选的实施方案中，本发明提供的成套药盒还包含有效量的抗VEGF-A抗体。
在一个实施方案中，成套药盒中各个活性成分分别储存在单独的容器中。
在一个实施方案中，成套药盒中的抗PD-1抗体包含SEQ ID NO:1、2、3所示的HCDR1、HCDR2、HCDR3和SEQ ID NO:4、5、6所示的LCDR1、LCDR2、LCDR3。
在一个实施方案中，成套药盒中的抗PD-1抗体包含SEQ ID NO:7所示的VH和SEQ ID NO:8所示的VL。
在一个实施方案中，成套药盒中的抗PD-1抗体包含SEQ ID NO:9所示的重链和SEQ ID NO:10所示的轻链。
在一个实施方案中，成套药盒包括50mg、60mg、70mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg或500mg的抗PD-1抗体。
在一个实施方案中，成套药盒中的抗VEGF-A抗体为贝伐珠单抗。
在一个实施方案中，成套药盒包括60mg、120mg、180mg、240mg、300mg、360mg、420mg、480mg、540mg、600mg、720mg、840mg、900mg、960mg、1080mg或1200mg的抗VEGF-A抗体。
在一个实施方案中，成套药盒中的化学治疗剂优选培美曲塞、顺铂。
在一个实施方案中，所述成套药盒中的培美曲塞的剂量为200-600mg/m 2，例如200mg/m 2、300mg/m 2、400mg/m 2、450mg/m 2、500mg/m 2，或任何现有技术中的常规剂量。
在一个实施方案中，所述成套药盒中的顺铂的剂量为50-100，例如50mg/m 2、60mg/m 2、70mg/m 2、75mg/m 2、80mg/m 2，或任何现有技术中的常规剂量。
在一个实施方案中，成套药盒还包含包装插页，其印有关于在个体中使用抗PD-1抗体和抗VEGF-A抗体的组合预防或治疗癌症的说明书。
4)治疗方法
在一个实施方式中，本发明提供了一种预防或治疗受试者的肿瘤的方法，包括向所述受试者施用本发明的药物组合或成套药盒。
在一个实施方式中，所述治疗方法包括2个给药阶段：
(i)第一阶段，向受试者依次施用抗PD-1抗体，抗VEGF-A抗体和化学治疗剂；或向受试者依次施用抗PD-1抗体和化学治疗剂，和
(ii)第二阶段，向受试者依次施用抗PD-1抗体，抗VEGF-A抗体和化学治疗剂；或向受试者依次施用抗PD-1抗体和化学治疗剂。
在一个实施方式中，所述治疗方法包括2个给药阶段：
(i)第一阶段，向受试者依次施用抗PD-1抗体，抗VEGF-A抗体，培美曲塞和铂类药物；或向受试者依次施用抗PD-1抗体，培美曲塞和铂类药物，和
(ii)第二阶段，向受试者依次施用抗PD-1抗体，抗VEGF-A抗体和培美曲塞；或向受试者依次施用抗PD-1抗体和培美曲塞。
在一个实施方式中，铂类药物为顺铂。
在一个实施方式中，第一阶段为联合治疗期，第二阶段为维持治疗期。
在一个优选实施方式中，所述治疗方法包括：
(i)第一阶段联合治疗期，向受试者依次施用抗PD-1抗体，抗VEGF-A抗体，培美曲塞和铂类药物，和
(ii)第二阶段维持治疗期，向受试者依次施用抗PD-1抗体，抗VEGF-A抗体和培美曲塞。
在一个实施方式中，铂类药物为顺铂。
在一个具体实施方式中，所述抗VEGF-A抗体的单次给药剂量为15mg/kg，抗PD-1抗体的单次给药剂量为200mg，培美曲塞的单次给药剂量为500mg/m 2，顺铂的单次给药剂量为75mg/m 2。
在另一个实施方式中，联合治疗期包括4个周期，其中每三周为一个治疗周期，在每个周期的第一天依次给药。
在一个实施方式中，受试者最多接受4个周期的顺铂
在一个实施方式中，持续给药其它药物成分，例如抗PD-1抗体，抗VEGF-A抗体和培美 曲塞。
在一个实施方式中，所有受试者持续治疗时间最多为24个月。
在一个实施方式中，所述肿瘤是肺癌，优选地，所述肺癌是非小细胞肺癌，更优选地，所述非小细胞肺癌为经表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗失败的EGFR突变的局部晚期或转移性非鳞非小细胞肺癌。
在一个实施方式中，本发明提供的治疗方法获得如下益处：
(a)受试者无进展生存期(PFS)有所改善，例如相对于采用培美曲塞和顺铂的化疗治疗组具有明显改善的无进展生存期；
(b)受试者的客观缓解率(ORR)有所改善，例如相对于采用培美曲塞和顺铂的化疗治疗组具有明显改善的无进展生存期；
(c)受试者的响应持续时间(DOR)有所改善，例如相对于采用培美曲塞和顺铂的化疗治疗组具有明显改善的无进展生存期。
5)用途
在一个实施方式中，本发明提供了上述药物组合或成套药盒用于治疗肿瘤的用途。
在另一个实施方式中，本发明提供了上述药物组合或成套药盒在制备预防或治疗肿瘤的药物中的用途。
在一个实施方式中，所述肿瘤是肺癌，优选地，所述肺癌是非小细胞肺癌，更优选地，所述非小细胞肺癌为经表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗失败的EGFR突变的局部晚期或转移性非鳞非小细胞肺癌。
在一个实施方式中，本发明的药物组合或成套药盒可以获得如下益处：
(a)受试者无进展生存期(PFS)有所改善，例如相对于采用培美曲塞和顺铂的化疗治疗组具有明显改善的无进展生存期；
(b)受试者的客观缓解率(ORR)有所改善，例如相对于采用培美曲塞和顺铂的化疗治疗组具有明显改善的无进展生存期；
(c)受试者的响应持续时间(DOR)有所改善，例如相对于采用培美曲塞和顺铂的化疗治疗组具有明显改善的无进展生存期。
具体实施方式
实施例1
①受试药物
抗PD-1抗体，信迪利单抗注射液，信达生物制药(苏州)有限公司，规格：10ml:100mg。
抗VEGF-A抗体，贝伐珠单抗注射液，生产企业：信达生物制药(苏州)有限公司。规格：4ml:100mg。
培美曲塞：500mg/瓶
顺铂：10mg或20mg的多剂量瓶装
安慰剂1：枸橼酸钠(二水)：5.88mg/ml
氯化钠：2.92mg/ml
组氨酸：3.73mg/ml
甘露醇：30.06mg/ml
依地酸二钠：0.0075mg/ml
聚山梨酯80：0.2mg/ml
枸橼酸(一水)：适量，调节pH至6.0
安慰剂2：醋酸钠Sodium acetate：1.64mg/ml
山梨醇Sorbitol：50mg/ml
聚山梨酯80Polysorbate 80：2mg/ml
冰醋酸Glacial acetic acid：调节pH至5.2
②入组标准
1)签署书面知情同意书；
2)年龄≥18岁且≤75岁的男性或女性；
3)根据国际肺癌研究协会和美国癌症分类联合委员会第8版肺癌TNM分期，经组织学或细胞学证实的不能手术治疗且不能接受根治性同步放化疗局部晚期或转移性(ⅢB、ⅢC或Ⅳ期)的非鳞NSCLC；
4)EGFR-TKI治疗前经肿瘤组织学或细胞学或血液学证实存在EGFR突变；
5)EGFR-TKI治疗失败(基于RECIST V1.1，经影像学证实的疾病进展)后，符合下述任一要求：
a)既往接受第1代或第2代EGFR-TKI(如：埃克替尼、吉非替尼、厄洛替尼、阿法替尼或其它已在中国上市的第1代或第2代EGFR-TKI)治疗并失败，需要经组织学证实EGFR20外显子T790M突变阴性；
b)既往接受第1代或第2代EGFR-TKI(如：埃克替尼、吉非替尼、厄洛替尼、阿法替尼)治疗，在治疗中或治疗失败后经组织学或血液学证实存在EGFR 20外显子T790M突变阳 性，后续接受第3代EGFR-TKI(如：奥希替尼或其它已在中国上市的第3代EGFR-TKI)治疗并失败；(如果第1代或第2代EGFR-TKI治疗失败后无T790M检测结果，必需满足服用已上市第3代EGFR-TKI超过6个月后疾病进展；如果第1代或第2代EGFR-TKI治疗失败后无T790M检测结果，服用临床研发阶段的第3代EGFR-TKI疾病进展后改用已上市的第3代EGFR-TKI治疗仍有效，必需满足后者治疗时间超过6个月后发生疾病进展)；
c)既往初诊EGFR突变NSCLC时即接受第3代EGFR-TKI(如：奥希替尼或其它已在中国上市的第3代EGFR-TKI)治疗并失败；
6)必须至少有一个可测量病灶作为靶病灶(根据RECIST V1.1)，位于既往放疗照射野内或局部治疗后的可测量病灶如果证实发生进展，亦可选为靶病灶；
7)东部肿瘤协作组体力状态评分(ECOG PS)为0～1分；
8)预计生存时间≥3个月；
9)筛选时的实验室结果必须符合以下要求(获得实验室检查结果的前14天内不允许施用任何血液成分、细胞生长因子及其他静脉或皮下给药的纠正治疗药物)：
a)血常规：中性粒细胞绝对计数(ANC)≥1.5×10 9/L，血小板计数(PLT)≥100×10 9/L，血红蛋白(HGB)≥90g/L(7日内无输血或无促红细胞生成素依赖性)；
b)肝功能：总胆红素(TBIL)≤1.5倍正常值上限(ULN)；不存在肝转移受试者其丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)≤2.5倍ULN，肝转移受试者其ALT和AST≤5倍ULN；
c)肾功能：血清肌酐(Cr)≤1.5倍ULN或Cr清除率≥60mL/min(Cockcroft-Gault公式)，且尿常规检测结果显示尿蛋白(UPRO)＜2+或24小时尿蛋白定量＜1g；
d)研究治疗前7天内，国际标准化比率(INR)≤1.5倍ULN，且部分促凝血酶原时间(PTT)或活化部分凝血活酶时间(APTT)≤1.5倍ULN；
10)对于育龄期女性受试者，应在接受首次研究药物给药(第1周期，第1天)之前的3天内呈尿液或血清妊娠试验阴性。如果尿液妊娠试验结果无法确认为阴性，则要求进行血液妊娠试验；
③治疗方案
本研究是一项评估信迪利单抗±贝伐珠单抗联合培美曲塞和顺铂用于经表皮生长因子受 体酪氨酸激酶抑制剂(EGFR-TKI)治疗失败的EGFR突变的局部晚期或转移性非鳞非小细胞肺癌患者的有效性和安全性的随机、双盲、多中心Ⅲ期临床研究(ORIENT-31)。
本研究计划入组630例EGFR-TKI治疗失败的EGFR突变的ⅢB、ⅢC期和Ⅳ期非鳞NSCLC患者。既往接受过EGFR-TKI治疗失败的局部晚期或转移性非鳞非小细胞肺癌患者，签署知情同意后，筛选合格受试者在第一阶段以1：1：1的比例随机分配到试验组A(信迪利单抗+贝伐珠单抗+培美曲塞+顺铂)或试验组B(信迪利单抗+安慰剂2+培美曲塞+顺铂)或对照组C(安慰剂1+安慰剂2+培美曲塞+顺铂)中；在第二阶段以2：2：1的比例随机分配到试验组A(信迪利单抗+贝伐珠单抗+培美曲塞+顺铂)或试验组B(信迪利单抗+安慰剂2+培美曲塞+顺铂)或对照组C(安慰剂1+安慰剂2+培美曲塞+顺铂)。分层因素包括：性别(男性或女性)和脑转移(存在或不存在)。本研究每组的治疗分为联合治疗期及维持治疗期，具体如下：
第一阶段：
试验组A(N＝160)：
联合治疗期：信迪利单抗200mg+贝伐珠单抗+培美曲塞+顺铂，Q3W*4，
维持治疗期：信迪利单抗200mg+贝伐珠单抗+培美曲塞，Q3W*4
试验组B(N＝160)：
联合治疗期：信迪利单抗200mg+安慰剂2+培美曲塞+顺铂，Q3W*4
维持治疗期：信迪利单抗200mg+安慰剂2+培美曲塞，Q3W*4
对照组C(N＝160)：
联合治疗期：安慰剂1+安慰剂2+培美曲塞+顺铂，Q3W*4
维持治疗期：安慰剂1+安慰剂2+培美曲塞，Q3W*4
第二阶段：
试验组A(N＝60)：
联合治疗期：信迪利单抗200mg+贝伐珠单抗+培美曲塞+顺铂，Q3W*4
维持治疗期：信迪利单抗200mg+贝伐珠单抗+培美曲塞，Q3W*4
试验组B(N＝60)：
联合治疗期：信迪利单抗200mg+安慰剂2+培美曲塞+顺铂，Q3W*4
维持治疗期：信迪利单抗200mg+安慰剂2+培美曲塞，Q3W*4
对照组C(N＝30)：
联合治疗期：安慰剂1+安慰剂2+培美曲塞+顺铂，Q3W*4
维持治疗期：安慰剂1+安慰剂2+培美曲塞，Q3W*4
具体治疗方案如下表所示：
Figure PCTCN2022132913-appb-000006
④试验结果
第一次期中分析，中位随访时间9.8个月。
Figure PCTCN2022132913-appb-000007
Figure PCTCN2022132913-appb-000008
第二次期中分析，中位随访时间：13.1个月。
Figure PCTCN2022132913-appb-000009
Figure PCTCN2022132913-appb-000010
试验结果显示，在意向治疗(ITT)人群中，基于独立影像评估委员会(IRRC)评估，信迪利单抗注射液和贝伐珠单抗注射液联合化疗组(试验组A)、信迪利单抗注射液联合化疗组(试验组B)、化疗组(对照组C)的中位无进展生存期(PFS)(95％CI)分别为6.9个月(6.0,9.3)、5.6个月(4.7,6.9)、4.3个月(4.1,5.4)。试验组A对比对照组C获得了显著且具有临床意义的PFS延长(HR＝0.464，95％CI:0.337,0.639；P＜0.0001)，达到预设的优效性界值；试验组B对比对照组C的PFS在第二次期中分析时达到优效性(HR＝0.718，95％CI:0.549,0.941；P＝0.0155)，所以信迪利单抗注射液联合化疗基础上叠加贝伐珠单抗注射液具有临床意义的PFS获益，优于培美曲塞和顺铂化疗组合，较信迪利单抗联合化疗三药组合也呈现更优的获益趋势。此外，试验组A对比对照组C的关键次要疗效终点客观缓解率(ORR)、缓解持续时间(DOR)均有提高，研究者评估的PFS、ORR、DOR结果与IRRC评估结论一致。

Claims (17)

  1. 一种药物组合，其包括(1)抗PD-1抗体，和(2)一种或多种化学治疗剂，其中所述抗PD-1抗体包含重链和轻链，其中所述重链包含HCDR1、HCDR2、HCDR3，所述HCDR1包含SEQ ID NO:1所示的氨基酸或由其组成；HCDR2包含SEQ ID NO:2所示的氨基酸或由其组成；HCDR3包含SEQ ID NO:3所示的氨基酸或由其组成；所述轻链包含LCDR1、LCDR2、LCDR3，所述LCDR1包含SEQ ID NO:4所示的氨基酸或由其组成；LCDR2包含SEQ ID NO:5所示的氨基酸或由其组成；LCDR3包含SEQ ID NO:6所示的氨基酸或由其组成。
  2. 权利要求1的药物组合，其中所述抗PD-1抗体包含VH和VL，其中所述VH包含SEQ ID NO:7所示的氨基酸序列，或包含与SEQ ID NO:7具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一性的氨基酸序列或由SEQ ID NO:7组成，所述VL包含SEQ ID NO:8所示的氨基酸序列，或包含与SEQ ID NO:8具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一性的氨基酸序列，或由SEQ ID NO:8组成。
  3. 权利要求1-2中任一项的药物组合，其中所述抗PD-1抗体包含重链和轻链，其中所述重链包含SEQ ID NO:9所示的氨基酸序列，或包含与SEQ ID NO:9具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一性的氨基酸序列，或由SEQ ID NO:9组成，所述轻链包含SEQ ID NO:10所示的氨基酸序列，或包含与SEQ ID NO:10具有至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一性的氨基酸序列或由SEQ ID NO:10组成。
  4. 权利要求1-3中任一项的药物组合，其还包含抗VEGF-A抗体。
  5. 权利要求1-4中任一项的药物组合，其中所述抗VEGF-A抗体为贝伐珠单抗。
  6. 权利要求1-5中任一项的药物组合，其中所述化学治疗剂为培美曲塞、铂类药物，优选地，所述铂类为顺铂。
  7. 权利要求1-6中任一项的药物组合，其中抗VEGF-A抗体剂量选自1-20mg/kg，优选1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg、12mg/kg、14mg/kg、15mg/kg、16mg/kg、18mg/kg、20mg/kg，更优选15mg/kg；或抗VEGF-A抗体剂量选自60-1200mg，优选60mg、120mg、180mg、240mg、300mg、360mg、420mg、480mg、 540mg、600mg、720mg、840mg、900mg、960mg、1080mg、1200mg，更优选900mg；所述抗PD-1抗体剂量选自50-500mg，优选50mg、60mg、70mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg，更优选200mg。
  8. 权利要求1-7中任一项的药物组合，每周一次、每两周一次、每三周一次、每四周一次、每五周一次或每六周一次施用所述药物组合，优选为每三周一次施用所述药物组合，例如通过静脉注射所述抗体。
  9. 权利要求1-8中任一项的药物组合，所述抗VEGF-A抗体，所述抗PD-1抗体和一种或多种化学治疗剂同时给药、分开给药或依次给药，优选依次给药。
  10. 权利要求1-9中任一项的药物组合，其中所述依次给药是先施用抗PD-1抗体后再施用抗VEGF-A抗体，随后再施用化学治疗剂；优选，施用抗PD-1抗体后0.5-24小时再施用抗VEGF-A抗体，优选使用VEGF-A抗体的时间为30～60分钟；在施用抗VEGF-A抗体后0.5-24小时再施用化学治疗剂。
  11. 一种成套药盒，其包含权利要求1-10任一项所述的有效量的抗PD-1抗体、有效量的化学治疗剂(优选培美曲塞、顺铂)，优选地还包括有效量的抗VEGF-A抗体；优选地，还包含包装插页，其印有关于在个体中使用抗PD-1抗体和抗VEGF-A抗体的组合预防或治疗癌症的说明书。
  12. 权利要求11的成套药盒，包括50mg、60mg、70mg、100mg、150mg、200mg、250mg、300、350、400mg、450mg或500mg的抗PD-1抗体和60mg、120mg、180mg、240mg、300mg、360mg、420mg、480mg、540mg、600mg、720mg、840mg、900mg、960mg、1080mg或1200mg抗VEGF-A抗体。
  13. 权利要求1-10中任一项所述的药物组合或权利要求11或12所述的成套药盒在制备预防或治疗肿瘤的药物中的用途；优选地，所述肿瘤是肺癌，优选地，所述肺癌是非小细胞肺癌，更优选地，所述非小细胞肺癌为经表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗失败的EGFR突变的局部晚期或转移性非鳞非小细胞肺癌。
  14. 一种治疗受试者的肿瘤的方法，包括向所述受试者施用权利要求1-10任一项所述的药物组合或权利要求11或12所述的成套药盒，其中按照以下步骤给药：
    (i)第一阶段，向受试者依次给予抗PD-1抗体、抗VEGF-A抗体、培美曲塞和铂类药物(优选顺铂)；或向受试者依次给予抗PD-1抗体、培美曲塞和铂类药物(优选顺铂)，
    (ii)第二阶段，向受试者依次给予抗PD-1抗体、抗VEGF-A抗体和培美曲塞；或向受试者依次给予抗PD-1抗体和培美曲塞，
    优选地，
    (i)第一阶段为联合治疗期，向受试者依次给予抗PD-1抗体、抗VEGF-A抗体、培美曲塞和铂类药物(优选为顺铂)，和
    (ii)第二阶段维为持治疗期，向受试者依次给予抗PD-1抗体，抗VEGF-A抗体和培美曲塞。
  15. 权利要求14所述的治疗方法，其中所述抗VEGF-A抗体的单次给药剂量为15mg/kg，抗PD-1抗体的单次给药剂量为200mg，培美曲塞的单次给药剂量为500mg/m 2，顺铂的单次给药剂量为75mg/m 2。
  16. 权利要求14或15所述的治疗方法，其中联合治疗期包括4个周期，其中每三周为一个治疗周期，在每个周期的第一天依次给药，其中最多施用4个周期的顺铂，其它药物在治疗期持续给药，其中所有受试者持续治疗时间最多为24个月。
  17. 如权利要求14-16任一项所述的治疗方法，其中所述肿瘤是肺癌，优选地，所述肺癌是非小细胞肺癌，更优选地，所述非小细胞肺癌为经表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗失败的EGFR突变的局部晚期或转移性非鳞非小细胞肺癌。
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